Dual expression of Atoh1 and Ikzf2 promotes transformation of adult cochlear supporting cells into outer hair cells

Mammalian cochlear outer hair cells (OHCs) are essential for hearing. Severe hearing impairment follows OHC degeneration. Previous attempts at regenerating new OHCs from cochlear supporting cells (SCs) have been unsuccessful, notably lacking expression of the key OHC motor protein, Prestin. Thus, regeneration of Prestin+ OHCs represents a barrier to restore auditory function in vivo. Here, we reported the successful in vivo conversion of adult mouse cochlear SCs into Prestin+ OHC-like cells through the concurrent induction of two key transcriptional factors known to be necessary for OHC development: Atoh1 and Ikzf2. Single-cell RNA sequencing revealed the upregulation of 729 OHC genes and downregulation of 331 SC genes in OHC-like cells. The resulting differentiation status of these OHC-like cells was much more advanced than previously achieved. This study thus established an efficient approach to induce the regeneration of Prestin+ OHCs, paving the way for in vivo cochlear repair via SC transdifferentiation.

W-representation of Rainbow tensor model

We analyze the rainbow tensor model and present the Virasoro constraints, where the constraint operators obey the Witt algebra and null 3-algebra. We generalize the method of W-representation in matrix model to the rainbow tensor model, where the operators preserving and increasing the grading play a crucial role. It is shown that the rainbow tensor model can be realized by acting on elementary function with exponent of the operator increasing the grading. We derive the compact expression of correlators and apply it to several models, i.e., the red tensor model, Aristotelian tensor model and r = 4 rainbow tensor model. Furthermore, we discuss the case of the non-Gaussian red tensor model and present a dual expression for partition function through differentiation.

Comparing Astrocytic Gap Junction of Genetic Absence Epileptic Rats with Control Rats: An Experimental Study

The synchronization of astrocytes via gap junctions (GJ) is a crucial mechanism in epileptic conditions, contributing to the synchronization of the neuronal networks. Little is known about the endogenous response of GJ in genetic absence epileptic animal models. We evaluated and quantified astrocyte GJ protein connexin 30 (Cx30) and 43 (Cx43) in the somatosensory cortex (SSCx), ventrobasal (VB), centromedian (CM), lateral geniculate (LGN) and thalamic reticular (TRN) nuclei of thalamus of genetic absence epilepsy rats from Strasbourg (GAERS), Wistar albino glaxo rats from Rijswijk (WAG/Rij) and control Wistar animals using immunohistochemistry and Western Blot. The Cx30 and Cx43 immunopositive astrocytes in per unite area were quantified for each region of the three animal strains. Further, Cx30 and Cx43 Western Blot was applied to the tissue samples from the same regions of the three strain. The number of Cx30 immunopositive astrocytes showed significant increase in both GAERS and WAG/Rij compared to control Wistar in all brain regions studied except LGN of WAG/Rij animals. Furthermore, Cx43 in both GAERS and WAG/Rij showed significant increase in SSCx, VB and TRN. The percentage of dual expression of Cx30 and Cx43 in the same astrocyte ranged between 17-100% for the 5 brain regions of the 3 animal strains studied. The protein expression of both Cx30 and Cx43 in the two epileptic strain showed an increase compared to Wistar control animals. The significant increase in the astrocytic GJ proteins Cx30 and Cx43 and the differences in the dual expression of Cx30 and Cx43 in the genetically absence epileptic strains compared to control animals may suggest that astrocytic Cx’s may be involved in the mechanism of absence epilepsy. Increased number of astrocytic Cx’s in GAERS and WAG/Rij may represent a compensatory response of the thalamocortical circuitry to the absence seizures or may be related to the production of absence seizures.

Dual expression of Atoh1 and Ikzf2 promotes transformation of adult cochlear supporting cells into outer hair cells

ABSTRACTMammalian cochlear outer hair cells (OHCs) are essential for hearing. OHC degeneration causes severe hearing impairment. Previous attempts of regenerating new OHCs from cochlear supporting cells (SCs) had yielded cells lacking Prestin, a key motor protein for OHC function. Thus, regeneration of Prestin+ OHCs remains a challenge for repairing OHC damage in vivo. Here, we reported that successful in vivo conversion of adult cochlear SCs into Prestin+ OHC-like cells could be achieved by simultaneous expression of Atoh1 and Ikzf2, two key transcriptional factors necessary for OHC development. New OHC-like cells exhibited upregulation of hundreds of OHC genes and downregulation of SC genes. Single cell transcriptomic analysis demonstrated that the differentiation status of these OHC-like cells was much more advanced than previously achieved. Thus, we have established an efficient approach to promote regeneration of Prestin+ OHCs and paved the way for repairing damaged cochlea in vivo via transdifferentiation of SCs.

Escape from X chromosome inactivation and female bias of autoimmune diseases

Generally, autoimmune diseases are more prevalent in females than males. Various predisposing factors, including female sex hormones, X chromosome genes, and the microbiome have been implicated in the female bias of autoimmune diseases. During embryogenesis, one of the X chromosomes in the females is transcriptionally inactivated, in a process called X chromosome inactivation (XCI). This equalizes the impact of two X chromosomes in the females. However, some genes escape from XCI, providing a basis for the dual expression dosage of the given gene in the females. In the present review, the contribution of the escape genes to the female bias of autoimmune diseases will be discussed.

Prognostic Stratification of Baseline Total Metabolic Tumor Volume on PET/CT Combined with MYC/Bcl-2 Dual Expression in Patients with Primary Gastrointestinal Diffuse Large B-Cell Lymphoma

Purpose: The aim of the present study was to explore whether pretreatment total metabolic tumor volume (TMTV) combined with MYC/BCL-2 dual expression (DE) would improve the prognostic stratification of patients who were newly diagnosed with primary gastrointestinal diffuse large B-cell lymphoma (PGI-DLBCL).Materials and methods: Eighty-three patients between March 2011 and November 2019, diagnosed with PGI-DLBCL prior to treatment, were included in this retrospective study. Baseline TMTV on PET/CT scans were calculated automatically using the boundaries of voxels presenting a SUVmax≥2.5. Expression of MYC/BCL-2 were detected at protein levels via immunohistochemistry（IHC）. The distributions of Progression-free survival (PFS) and overall survival (OS) rates were estimated using the Kaplan-Meier method and differences were compared using a log-rank test followed by multivariate analysis using the Cox proportional hazards model.Results: TMTV and DE were significantly associated with a worse PFS and OS. Multivariate analysis revealed that TMTV (HR=6.090, P<0.001) and DE (HR=2.761, P=0.021) were each independent predictors of PFS, whereas TMTV (HR=9.512, P<0.001) was the only independent predictor of OS. A monogram comprised of TMTV and DE expression identified four groups with very different outcomes: (PFS:χ2=32.178, P<0.001; OS:χ2=23.091, P<0.001): low-risk group (low TMTV and non-DE, 46 patients); low-intermediate risk group (low TMTV and DE, 16 the patients); high-intermediate risk group (high TMTV and non-DE, 12 patients); and high-risk group (high TMTV and DE patients, 9 patients). Conclusions: TMTV and DE independently predicted survival outcomes in PGI-DLBCL patients. Furthermore, our findings suggest that combination of TMTV and DE may further improve the ability of clinicians to stratify patients in terms of differential prognoses.